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XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [ChIP-seq]

ABSTRACT: X-chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X-chromosome in cis to mediate chromosome-wide gene silencing. In female naïve human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration and XCI does not occur, raising questions about XIST’s function. We found that XIST spreads across the X-chromosome and induces dampening of X-linked gene expression in naïve hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X-chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. Dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our results identify XIST as the regulator of X-chromosome dampening, uncover an evolutionarily conserved trans-acting role of XIST/Xist, and reveal a correlation between XIST/Xist dispersal and autosomal targeting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241442 | GEO | 2023/12/15

REPOSITORIES: GEO

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XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [RNA-seq]

Project description:X-chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X-chromosome in cis to mediate chromosome-wide gene silencing. In female naïve human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration and XCI does not occur, raising questions about XIST’s function. We found that XIST spreads across the X-chromosome and induces dampening of X-linked gene expression in naïve hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X-chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences on autosomes. Dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our results identify XIST as the regulator of X-chromosome dampening, uncover an evolutionarily conserved trans-acting role of XIST/Xist, and reveal a correlation between XIST/Xist dispersal and autosomal targeting.

2023-12-15 | GSE241438 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [CUT&Tag]

2023-12-15 | GSE241443 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells

2023-12-13 | GSE241444 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [RAP-seq_human]

2023-12-15 | GSE241439 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [scRNA-seq]

2023-12-15 | GSE241441 | GEO

XIST directly regulates X-linked and autosomal genes in naïve human pluripotent cells [RAP-seq_mouse]

2023-12-15 | GSE241440 | GEO

The role of early chromatin changes in X chromosome inactivation

Project description:During development, transcriptional and chromatin modification changes co-occur but the order and causality of events often remain unclear. We explore the interrelationship of these processes using the paradigm of X-chromosome inactivation (XCI). We initiate XCI in female, mouse embryonic stem cells by inducing Xist expression and monitor changes in transcription and chromatin by allele-specific TT-seq and ChIP-seq respectively. An unprecedented temporal resolution enabled identification of the earliest chromatin alterations during XCI. We demonstrate that HDAC3 interacts with both NCOR1 and NCOR2 and is pre-bound on the X chromosome where it deacetylates histones to promote efficient gene silencing. We also reveal the choreography of polycomb accumulation following Xist RNA coating, with PRC1-associated H2AK119Ub preceding PRC2-associated H3K27me3. Furthermore, polycomb-associated marks accumulate initially at large, intergenic domains and then spreads into genes but only in the context of gene silencing. Our results provide the hierarchy of chromatin events during XCI and demonstrate that some chromatin changes play key roles in mediating transcriptional silencing.

2019-01-17 | PXD011344 | Pride

High-resolution chromosomal maps of Xist RNA reveal a two-step spreading mechanism during X-inactivation

Project description:The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes. During XCI, Xist coats the future inactive X (Xi) and recruits Polycomb Repressive Complex 2 (PRC2) to the X-inactivation center (Xic). Currently unclear is how Xist spreads silencing on a 150 Mb scale. Here we generate high-resolution maps of Xist binding across a developmental time course using CHART-seq. In female cells undergoing XCI de novo, Xist follows a two-step mechanism in which it initially targets gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but frequently concentrates near escapee boundaries. Xist binding was linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), suggesting co-migration of Xist and PRC2. Interestingly, when the Xi is acutely stripped of Xist in post-XCI cells, Xist recovers quickly within both gene-rich and -poor domains on a time scale of hours instead of days, suggesting a previously primed Xi chromatin state. We conclude that Xist spreading takes on distinct stage-specific forms: During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and -poor regions. Capture hybridization analysis of RNA targets (CHART) and input samples of (differentiating) mouse embryonic stem (ES) cells and immortalized mouse embryonic fibroblasts (MEF) using paired-end 75 nt reads on Illumina HiSeq2500, with 2 replicates per sample (# of samples). RNA-seq of the same cell lines with 50 nt reads on Illumina HiSeq2000, with 2 replicates per sample (2 samples, 4 datasets total). CHIP-seq: Data from GSE36905 was aligned and processed as CHART-seq samples. Resulting coverage tracks (EZH2/K27me3) are linked directly to GSE48649 (bedGraphs linked below).

2013-11-04 | E-GEOD-48649 | biostudies-arrayexpress

The efficiency of Xist-mediated silencing of X-linked and autosomal genes is determined by the genomic environment

Project description:Xist is indispensable for X chromosome inactivation (XCI) in female mammalian cells. However, how Xist RNA directs chromosome-wide transcriptional inactivation of the X chromosome is largely unknown. Here, to study chromosome inactivation by Xist, we generated a system where ectopic Xist expression can be induced from several genomic contexts in aneuploid mouse ES cells. We found that ectopic Xist expression from any location on the X chromosome faithfully recapitulated endogenous XCI, showing the potency of Xist to initiate XCI. Genes that escape XCI remain consistently transcriptionally active upon ectopic XCI, regardless of their position relative to Xist transgenes, and the enrichment of CTCF at their promoters is implicated in directing XCI escape. Xist expression from autosomes facilitates their transcriptional silencing to different degrees, and gene density in proximity of the Xist transcription locus plays a central role in determining the efficiency of gene inactivation. We also show that the enrichment of LINE elements together with a specific chromatin environment facilitates Xist-mediated silencing of both X-linked and autosomal genes. These findings provide new insights into the epigenetic mechanisms that mediate XCI and identify genomic features that promote Xist-mediated chromosome-wide gene inactivation

2017-07-04 | GSE92894 | GEO

High-resolution chromosomal maps of Xist RNA reveal a two-step spreading mechanism during X-inactivation

2013-11-04 | GSE48649 | GEO

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